The precise modes and timing of human immunodeficiency virus (HIV) infection in infants are not completely understood, but both in utero and perinatal infection are now well-documented, with a high percentage of infection estimated to occur near or during delivery. Thus, interventions that can be initiated during pregnancy or near the time of delivery may prevent infection in HIV-exposed infants. Important but unanswered questions include when potentially protective maternal antibodies cross the placenta, when to initiate maternal antiviral treatment, and how long to continue such treatments in neonates after delivery in order to prevent perinatal HIV infection. The goal of this project is to determine whether infection of infant macaques with simian immunodeficiency virus (SIV) can be prevented with the use of immunizations (whole inactivated SIV) during gestation or novel antiretroviral agents (PMPA, a non-toxic, nucleoside analog previously tested in rhesus neonates) when administered within the last week prior to delivery, or whether a combination of immunization and drug treatment is more efficacious. Our hypothesis is that transplacental transfer of maternal antibodies or PMPA to fetal rhesus macaques can prevent infection with a pathogenic SIV or a virulence-attenuated virus (SIV/HIV-1 chimera = SHIV). In the event SIV infection does occur, we hypothesize that viremia in peripheral blood will be low, antiviral immune responses will be vigorous, and disease will be delayed compared with historical data available from untreated, SIV-infected rhesus neonates. Currently, studies to evaluate efficacy of two prenatal regimens against infection or disease in newborns exposed orally or intravenously to SIV or SHIV are in progress one regimen consists of maternal immunization with whole-inactivated SIV, the other regimen involves maternal PMPA treatment. The results of these studies will be directly applicable to HIV-infected women and their offspring. *KEY* Pediatric simian AIDS, Oral SIV transmission, Perinatal HIV transmission, Coinfection, Antiretroviral therapy, Immunization in pregnancy